2. Academic Validation
  3. M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1

M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1

  • Cancer Lett. 2024 Jul 2:598:217085. doi: 10.1016/j.canlet.2024.217085.
Xiao-Jing Luo 1,  Yun-Xin Lu 2,  Yun Wang 2,  Runjie Huang 2,  Jia Liu 2,  Ying Jin 2,  Ze-Kun Liu 3,  Ze-Xian Liu 4,  Qi-Tao Huang 1,  Heng-Ying Pu 4,  Zhao-Lei Zeng 4,  Ruihua Xu 5,  Qi Zhao 6,  Qi-Nian Wu 7
Affiliations

Affiliations

  • 1 Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, PR China.
  • 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, PR China.
  • 3 Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, PR China.
  • 4 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
  • 5 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, PR China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, PR China. Electronic address: xurh@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China. Electronic address: zhaoqi@sysucc.org.cn.
  • 7 Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, PR China. Electronic address: wuqn@sysucc.org.cn.
PMID: 38964733 DOI: 10.1016/j.canlet.2024.217085
Abstract

LncRNA plays a crucial role in Cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal Cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. M6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440 nt) and T5 (2440-2743 nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.

Keywords

CRC; FAM83H-AS1; PTBP1; RNA splicing; m6A modification.

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